WO2011047107A1 - Administration entérale de dipeptide arginine-glutamine pour soutenir le développement rétinien, intestinal ou du système nerveux - Google Patents

Administration entérale de dipeptide arginine-glutamine pour soutenir le développement rétinien, intestinal ou du système nerveux Download PDF

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Publication number
WO2011047107A1
WO2011047107A1 PCT/US2010/052585 US2010052585W WO2011047107A1 WO 2011047107 A1 WO2011047107 A1 WO 2011047107A1 US 2010052585 W US2010052585 W US 2010052585W WO 2011047107 A1 WO2011047107 A1 WO 2011047107A1
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Prior art keywords
arginine
glutamine dipeptide
neonate
day
infant
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PCT/US2010/052585
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English (en)
Inventor
Joshua Anthony
Kristin Morris
Maria Grant
Joseph Neu
Original Assignee
Mead Johnson Nutrition Company
University Of Florida Research Foundation, Inc.
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Publication date
Application filed by Mead Johnson Nutrition Company, University Of Florida Research Foundation, Inc. filed Critical Mead Johnson Nutrition Company
Priority to SG2012016200A priority Critical patent/SG179040A1/en
Priority to CA2777240A priority patent/CA2777240A1/fr
Priority to CN2010800460132A priority patent/CN102573878A/zh
Priority to RU2012119719/15A priority patent/RU2012119719A/ru
Priority to IN2759DEN2012 priority patent/IN2012DN02759A/en
Priority to BR112012008814A priority patent/BR112012008814A2/pt
Priority to MX2012003725A priority patent/MX2012003725A/es
Priority to EP10824066A priority patent/EP2488191A1/fr
Publication of WO2011047107A1 publication Critical patent/WO2011047107A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the present disclosure relates to a method generally comprising enterally administering arginine-glutamine dipeptide in an amount that is effective to support retinal, intestinal, or nervous system development.
  • one embodiment of the present disclosure relates to a novel method for supporting retinal, intestinal, and/or nervous system development in a neonate.
  • the method generally includes enterally administering arginine-glutamine dipeptide to a neonate to provide an amount of arginine-glutamine dipeptide that is effective to support retinal, intestinal, and/or nervous system development, especially in an infant not otherwise receiving nutrition adequate in arginine and glutamine.
  • the present disclosure presents a novel infant formula.
  • the infant formula generally includes arginine-glutamine dipeptide in an amount that is effective to support one or more of retinal, intestinal, and nervous system development in a neonate.
  • the present disclosure is a human milk fortifier.
  • the human milk fortifier generally includes arginine-glutamine dipeptide in an amount that is effective to support one or more of retinal, intestinal, and nervous system development in a neonate.
  • the present disclosure is an infant nutritional supplement.
  • the infant nutritional supplement generally includes arginine- glutamine dipeptide in an amount that is effective to support one or more of retinal, intestinal, and nervous system development in a neonate.
  • compositions and practicing of methods which support retinal, intestinal, and/or nervous system development, and the provision of compositions and practicing of methods that treat hyperoxia symptoms, prevent retinopathy of prematurity (ROP), and/or reduce the risk of developing necrotizing enterocolitis (NEC).
  • ROP retinopathy of prematurity
  • NEC necrotizing enterocolitis
  • Fig.1 is a bar chart showing the effect of enterally administering arginine- glutamine dipeptide in reducing the average nuclei per section of the eyes of neonatal mice exposed to hyperoxia to induce retinal angiogenesis at dosage levels of: zero (control); 1 g/kg -day; 2.5 g/kg -day; and 5 g/kg -day.
  • Fig. 2 is a bar chart quantifying the level of intestinal injury of neonatal mice under three different conditions: control; hyperoxic conditions; and hyperoxic conditions combined with arginine-glutamine dipeptide treatment.
  • Fig. 3 is a bar chart showing the effect of administering arginine- glutamine dipeptide in increasing Bcl-2 expression in the brain of neonatal mice exposed to hyperoxic conditions.
  • Fig. 4 is a bar chart showing the effect of administering arginine- glutamine dipeptide in decreasing brain caspase-3 activity in the brain of neonatal mice exposed to hyperoxic conditions.
  • compositions containing arginine- glutamine dipeptides and methods for administering the same.
  • the subject disclosure provides enteral administration of arginine-glutamine dipeptide to support retinal, intestinal, and/or nervous system development.
  • enteral means through or within the gastrointestinal, or digestive, tract, and “enteral administration” includes oral feeding, intragastric feeding, transpyloric administration, or any other introduction into the digestive tract.
  • enteral administration of certain amounts of arginine-glutamine dipeptide is effective for facilitating healthy brain development, preventing retinopathy of prematurity (ROP), decreasing intestinal damage, and/or reducing the risk of developing necrotizing enterocolitis (NEC).
  • ROP is a retinal blood vessel development disorder in premature infants.
  • NEC is a leading cause of mortality and morbidity in neonatal intensive care units.
  • a dipeptide is a molecule consisting of two amino acids joined by a single peptide bond.
  • the two amino acids utilized are arginine and glutamine.
  • arginine and glutamine are contemplated as useful in the present disclosure as: (1) free amino acids or salts; (2) precursors of such amino acids; or (3) prodrugs. Whereas most amino acids exist bound together in various proteins, free amino acids are unbound.
  • Amino acid precursors are substances from which the amino acids are formed.
  • a prodrug may be based on a particular amino acid and is a pharmacological substance administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into the active compound.
  • an arginine-glutamine dipeptide itself may be administered.
  • oligopeptides, peptides, proteins, protein hydrolysates, and any other materials that could serve as a source of the arginine-glutamine dipeptide may also be administered either as a substitute or an additive. Examples of such sources include peptides of polyarginine and polyglutamine, peptides containing blocks of polyarginine and polyglutamine, and peptides of alternating arginine and glutamine.
  • these prodrug formulations may be designed with, for example, cleavage sites adjacent to each side of the arginine-glutamine dipeptide so that the dipeptide is generated upon exposure to enzymes, acids, or other factors.
  • a polypeptide can be prepared with multiple arginine- glutamine dipeptides separated by cleavage sites. When the polypeptide is exposed to a cleaving factor, which breaks apart the polypeptide, it is separated into multiple arginine-glutamine dipeptides. This cleaving to create the dipeptide can be performed as part of a production process or in vivo as the result of, for example, digestive enzymes and/or acids.
  • the prodrug can be converted to a biologically active compound at a controlled rate via passive (such as by aqueous hydrolysis) mechanisms or biologically-mediated (such as biocatalytic or enzymatic) mechanisms.
  • passive such as by aqueous hydrolysis
  • biologically-mediated such as biocatalytic or enzymatic
  • the arginine-glutamine dipeptide provides the two amino acids in a dipeptide having improved water solubility, stability to sterilization, long-term stability, and bioavailability for humans and animals.
  • An advantage of the dipeptide is its increased stability over free glutamine, for example, resulting in much lower cyclisation of glutamine into undesirable pyro-glutamate.
  • the arginine-glutamine dipeptide of the present disclosure has an N- terminal amino acid, which is arginine, and a C-terminal amino acid, which is glutamine.
  • the arginine-glutamine dipeptide of the subject disclosure can be readily synthesized and/or formulated by a person skilled in the art having the benefit of the present disclosure.
  • the dipeptides can be purchased commercially from, for example, Bachem Biosciences, Inc., which sells an arginine-glutamine dipeptide salt.
  • the arginine-glutamine dipeptides can be of any purity or grade, and can be of a purity and grade that is suitable for inclusion in the diet of human infants.
  • the present disclosure is useful to support retinal, intestinal, and/or nervous system development in a neonate.
  • the term "neonate” as used herein means a newborn infant, including premature infants, postmature infants, and full term newborns. Premature infants are babies born before 37 weeks of gestation. Postmature infants are babies born 2 weeks or more after 37 weeks of gestation. Full- term infants are born within 37 to 39 weeks of gestation.
  • the neonate may be in need of support for retinal, intestinal, and/or nervous system development. A neonate may be in need of support for retinal, intestinal, and/or nervous system development, for example, after being placed in hyperoxic conditions. Hyperoxic conditions have higher than normal oxygen saturation levels. Premature infants are routinely placed in a hyperoxic environment for purposes of resuscitation and treatment of respiratory maladies.
  • Apoptotic neurodegeneration, abnormal vascularization, NEC, or other neurological deficits or infections may also be used to identify a neonate that may be in need of support for retinal, intestinal, and/or nervous system development.
  • a neonate is typically in need of such support if it exhibits, or is at risk for developing, such pathologies.
  • Premature infants and infants exposed to hyperoxic environments or other conditions that are known to increase the risk of neurological deficits or NEC are often in need of support for retinal, intestinal, and/or nervous system development.
  • the arginine-glutamine dipeptide described herein may be used to prevent neovascularization in the retinal vascular endothelium, thus supporting healthy retinal development. Because retinal development is believed to be correlative to cognitive development, this may also support normal cognitive functions in the neonate.
  • the arginine-glutamine dipeptides described herein may increase the expression of the protein Bel- 2 in the brain.
  • the protein Bcl-2 is an anti- apoptotic protein that resides in the outer mitochondrial membrane and the membrane of the endoplasmic reticulum. High levels of the Bcl-2 protein protect cells from early death by apoptosis (cell death). The Bcl-2 protein can suppress apoptosis by preventing the activation of the caspases that carry out the process.
  • the arginine-glutamine dipeptides described herein can decrease the level of caspases in the brain.
  • Caspases are protease enzymes that play essential roles in apoptosis and inflammation. Certain caspases cleave other protein substrates within cells, resulting in the apoptotic process. Decreased levels of caspase may promote nervous system development.
  • aqueous compositions can be prepared that contain at least one arginine-glutamine dipeptide. The dipeptide can be added to enteral formulations, which can include nutritional supplements.
  • the formulas, supplements, or nutritional solutions can contain, for example, carbohydrates, lipids, fats, stabilizers, amino acids, peptides (including dipeptides, oligopeptides, and/or polypeptides), and/or proteins, vitamins, minerals and trace elements.
  • the selection of the particular arginine-glutamine dipeptide formulation depends upon the particular use for the formulation.
  • the administration of the arginine-glutamine dipeptide, rather than administration of free amino acids permits administration of the same amount of amino acid residue in solutions, which are less hypertonic and, therefore, of lower osmolality.
  • the arginine-glutamine dipeptide may be enterally administered to a neonate.
  • the arginine-glutamine dipeptides described herein may reduce intestinal injury associated with enteral administration, thus protecting the structural integrity of the intestine.
  • intestinal injury includes inflammation, cellular damage, or any other event that compromises the physiological integrity of the intestine.
  • Enteral nutrition is safer and less expensive than total parenteral nutrition, which is the practice of feeding a person intravenously.
  • Enteral administration is the preferred route for maintaining the integrity of the gastrointestinal tract.
  • oral administration is desirable, because it is the normal method for infant nutrition and one that is understood and accepted by the infant and persons providing nutrition to the infant.
  • Enteral administration of the present arginine-glutamine dipeptide can be by any recognized method and can take place at any time.
  • Formulations containing the active agents can be given once a day or multiple times per day.
  • Administration of formulations containing the present arginine-glutamine dipeptide can be alternated with administration of formulations that do not contain the present arginine-glutamine dipeptide, or formulations that contain the present dipeptide at levels other than those that will provide arginine-glutamine dipeptide to the infant in a total amount of from about 100 mg/kg -day to about 1000 mg/kg -day.
  • the arginine-glutamine dipeptide of the present disclosure can be enterally administered to a neonate in any known and accepted form or manner.
  • An embodiment of the present disclosure is a composition that can be an infant formula, human milk fortifier, or a nutritional or dietary supplement, and combinations thereof.
  • the infant formula, human milk fortifier, or nutritional supplement of the present disclosure can be milk-based, soy-based, based on other food sources, or combinations thereof.
  • the composition may be prepared as a powder and/or a liquid for formulas prepared for infant populations. If in powder form or concentrate liquid form, the formula is diluted to normal strength with water to be in a form ready to consume.
  • the inventive composition may be prepared as a nutritionally complete diet by including necessary nutrients, including vitamins and minerals at acceptable levels.
  • the subject composition can be in the form of a dietary product such as an infant formula, milk substitute, and/or meal replacement or supplement.
  • One embodiment of the disclosure is a nutritional or dietary supplement that contains the arginine-glutamine dipeptide or a precursor thereof.
  • the dietary supplement is designed to be administered along with a food or nutritional composition, such as infant formula, and can either be intermixed with the food or nutritional composition prior to ingestion by the subject, or can be administered to the subject either before or after ingestion of a food or nutritional composition.
  • the subject dietary supplement contains an amount of arginine-glutamine dipeptide, or a precursor thereof, that is effective for the support of retinal, intestinal, and/or nervous system development.
  • the amount of the arginine-glutamine dipeptide or its salt or prodrug that is an effective amount is an amount sufficient to evoke the desired physiological response. This is generally an amount sufficient to produce lessening of one or more of the effects of apoptotic neurodegeneration or neurological morbidity, reduce the risk of developing NEC, positively influence normal retinal vascularization and/or have a prohibitive effect on the risk of developing ROP. In the case of apoptotic neurodegeneration, it is an amount sufficient to reduce neurological morbidity and/or to support normal cognitive development and motor outcomes in premature infants and/or other infants otherwise susceptible to neurological deficits in the immediate postnatal period.
  • the arginine-glutamine dipeptide is administered to a neonate in an amount that may be from about 0.001 to about 10,000 mg/kg -day (where the units of mg/kg -day refer to mg of the arginine- glutamine dipeptide per kg of infant body weight per day).
  • the effective amount can also be from about 100 mg/kg -day to about 1000 mg/kg -day, or from about 200 mg/kg -day to about 800 mg/kg -day, or from about 250 mg/kg -day to about 600 mg/kg -day, or from about 300 mg/kg -day to about 600 mg/kg -day, or from about 300 mg/kg -day to about 500 mg/kg -day, or in an amount of about 500 mg/kg -day.
  • the amount of the active ingredients by weight refers to the amount of the equimolar combination of the arginine-glutamine dipeptide, or the amount of their salts or precursors sufficient to provide the stated amount of dipeptide.
  • a novel infant formula containing the present arginine-glutamine dipeptide, or precursor thereof is nutritionally complete.
  • nutritionally complete it is meant that the composition contains adequate nutrients to sustain healthy human life for extended periods.
  • the infant formula of the disclosure contains ingredients which are designed to meet the nutritional needs of the human infant, namely a fat, protein, carbohydrate, and lipid source, a stabilizer, and other nutrients such as vitamins and minerals.
  • composition of the disclosure can contain an additional nitrogen source (i.e., amino acids and/or protein) such that the total amount of amino acids or protein may be between about 1 g/100 kilocalories (kcal) to about 10 g/100 kcal of total composition, in some embodiments about 2 g/100 kcal to about 6 g/100 kcal.
  • additional nitrogen source i.e., amino acids and/or protein
  • the amount of lipid source per 100 kcal of total composition may be greater than 0 g up to about 6 g, in some embodiments about 0.5 g to about 5.5 g, and in other embodiments about 2 g to about 5.5 g; and the amount of non-fiber carbohydrate source per 100 kcal of total composition may be about 5 g to about 20 g, and in some embodiments may be about 7.5 g to about 15 g.
  • infant formula is not meant to include natural milk, such as unmodified cow's milk, unmodified goat's milk, unmodified human milk, or any other unmodified natural product, but rather refers to a formulation made by man in whole or in part by intermixing two or more ingredients.
  • infant formula means a composition that satisfies the nutrient requirements of an infant by being a substitute for human milk.
  • the infant formula, human milk fortifier or infant nutritional supplement is in a powdered form.
  • infant formula, human milk fortifier or infant nutritional supplement may be in a liquid or ready-to-use form.
  • the infant formula for use in the present disclosure is nutritionally complete and contains suitable types and amounts of lipids, fats, carbohydrates, proteins, vitamins and minerals.
  • the amount of lipid or fat typically can vary from about 3 to about 7 g/100 kcal.
  • the amount of protein typically can vary from about 1 to about 5 g/100 kcal.
  • the amount of carbohydrate typically can vary from about 8 to about 12 g/100 kcal.
  • an additional protein source when included in the subject infant formula, it can be non-fat milk solids, a combination of non-fat milk solids and whey protein, a partial hydrolysate of non-fat milk and/or whey solids, soy protein isolates, or partially hydrolyzed soy protein isolates.
  • the infant formula can be casein predominant or whey predominant.
  • the carbohydrate source in the infant formula can be any suitable carbohydrate known in the art to be suitable for use in infant formulas.
  • Typical carbohydrate sources include sucrose, fructose, glucose, maltodextrin, lactose, corn syrup, corn syrup solids, rice syrup solids, rice starch, modified corn starch, modified tapioca starch, rice flour, soy flour, and the like.
  • the lipid source in the infant formula can be any lipid or fat known in the art to be suitable for use in infant formulas.
  • Typical lipid sources include milk fat, safflower oil, egg yolk lipid, olive oil, coconut oil, palm oil, palm kernel oil, soybean oil, sunflower oil, fish oil and fractions derived thereof such as palm olein, medium chain triglycerides (MCT), and esters of fatty acids wherein the fatty acids are, for example, arachidonic acid, linoleic acid, palmitic acid, stearic acid, docosahexaenoic acid, eicosapentaenoic acid, linolenic acid, oleic acid, lauric acid, capric acid, caprylic acid, caproic acid, and the like.
  • High oleic forms of various oils are also contemplated to be useful herein such as high oleic sunflower oil and high oleic safflower oil.
  • MCT contains higher concentrations of caprylic and capric acid than typically found in conventional oils, e.g., approximately three-fourths of the total fatty acid content is caprylic acid and one-fourth is capric acid.
  • the infant formula of the disclosure also may contain emulsifiers and stabilizers such as soy lecithin, carrageenan, combinations thereof, and the like.
  • the infant formula of the disclosure may optionally contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, immunoglobulins, combinations thereof, and the like.
  • the osmolality of the liquid infant formula of the disclosure (when ready to consume) may be between about 100 and 1100 mOsm/kg 3 ⁇ 40, in some embodiments, between about 200 and 700 mOsm/kg H2O.
  • the infant formula of the disclosure can be sterilized, if desired, by techniques known in the art, for example, heat treatment such as autoclaving or retorting, and the like.
  • the infant formula of the disclosure can be packaged in any type of container known in the art to be used for storing nutritional products such as glass, lined paperboard, plastic, coated metal cans, and the like.
  • the infant formula of the disclosure should be shelf stable after reconstitution.
  • shelf stable it is meant that the formula, in a form ready to consume, remains in a single homogenous phase (i.e., does not separate into more than one phase upon visual inspection) or that the thickener does not settle out as a sediment upon visual inspection after storage overnight in the refrigerator.
  • the formula of the disclosure also has the advantage of remaining fluid (i.e., does not gel into a solid mass when stored overnight in the refrigerator) .
  • infant formula can be used.
  • EnfalacTM, Enfamil®, Enfamil® Premature Formula, Enfamil® with Iron, Enfamil® LIPIL®, Lactofree®, Nutramigen®, Pregestimil®, and ProSobee® may be supplemented with suitable amounts of arginine-glutamine dipeptide and used in practice of the disclosure.
  • the infant formula, human milk fortifier, or infant nutritional supplement contains additional components which may include probiotics, prebiotics, or additional long chain polyunsaturated fatty acids (LCPUFAs).
  • probiotic means a microorganism that exerts beneficial effects on the health of the host. Any probiotic known in the art may be added, provided it is suitable for combination with the other components of the supplement.
  • the probiotic may be chosen from the group consisting of Lactobacillus and Bifidobacterium.
  • the probiotic can be Lactobacillus rhamnosus GG.
  • the infant formula, human milk fortifier, or infant nutritional supplement of the present disclosure additionally comprises at least one prebiotic.
  • prebiotic means a non-digestible food ingredient that stimulates the growth and/or activity of probiotics.
  • any prebiotic known in the art may be added, provided it is suitable for combination with the other components of the supplement.
  • the prebiotic can be selected from the group consisting of polydextrose, fructo-oligosaccharide, gluco- oligosaccharide, galacto-oligosaccharide, inulin, isomalto-oligosaccharide, xylo-oligosaccharide, lactulose, and combinations thereof.
  • the LCPUFA may be docosahexaenoic acid (DHA), arachidonic acid (ARA), and/or eicosapentaenoic acid (EPA).
  • DHA docosahexaenoic acid
  • ARA arachidonic acid
  • EPA eicosapentaenoic acid
  • the amount of ARA in the present disclosure may be from about 4 mg/100 kcal to about 100 mg/100 kcal. In another embodiment, the amount of ARA may be from about 10 mg/100 kcal to about 67 mg/100 kcal. In yet another embodiment, the amount of ARA may be from about 20 mg/100 kcal to about 50 mg/100 kcal. In a particular embodiment, the amount of ARA may be from about 25 mg/100 kcal to about 40 mg/100 kcal. In one embodiment, the amount of ARA is about 30 mg/100 kcal.
  • the weight ratio of ARA:DHA may be from about 1:3 to about 9:1. In one embodiment of the present disclosure, this ratio is from about 1:2 to about 4:1. In yet another embodiment, the ratio is from about 2:3 to about 2:1. In one particular embodiment the ratio is about 2:1. In another particular embodiment of the disclosure, the ratio is about 1:1.5. In other embodiments, the ratio is about 1:1.3. In still other embodiments, the ratio is about 1:1.9. In a particular embodiment, the ratio is about 1.5:1. In a further embodiment, the ratio is about 1.47:1.
  • the level of DHA may be between about 0.0% and 1.00% of fatty acids, by weight. In other embodiments, the level of DHA may be about 0.32% by weight. In some embodiments, the level of DHA may be about 0.33% by weight. In another embodiment, the level of DHA may be about 0.64% by weight. In another embodiment, the level of DHA may be about 0.67% by weight. In yet another embodiment, the level of DHA may be about 0.96% by weight. In a further embodiment, the level of DHA may be about 1.00% by weight.
  • the level of ARA may be between 0.0% and 0.67% of fatty acids, by weight. In another embodiment, the level of ARA may be about 0.67% by weight. In another embodiment, the level of ARA may be about 0.5% by weight. In yet another embodiment, the level of DHA may be between about 0.47% and 0.48% by weight.
  • the amount of DHA may be from about 2 mg/100 kcal to about 100 mg/100 kcal. In another embodiment, the amount of DHA may be from about 5 mg/100 kcal to about 75 mg/100 kcal. In yet another embodiment, the amount of DHA may be from about 15 mg/100 kcal to about 60 mg/100 kcal.
  • the amount of ARA may be from about 4 mg/100 kcal to about 100 mg/100 kcal. In another embodiment, the amount of ARA may be from about 10 mg/100 kcal to about 67 mg/100 kcal. In yet another embodiment, the amount of ARA may be from about 20 mg/100 kcal to about 50 mg/100 kcal. In a particular embodiment, the amount of ARA may be from about 25 mg/100 kcal to about 40 mg/100 kcal. In one embodiment, the amount of ARA is about 30 mg/100 kcal.
  • the effective amount of DHA may be from about 3 mg per kg of body weight per day to about 150 mg per kg of body weight per day. In one embodiment of the disclosure, the amount is from about 6 mg per kg of body weight per day to about 100 mg per kg of body weight per day. In another embodiment the amount is from about 15 mg per kg of body weight per day to about 60 mg per kg of body weight per day.
  • the effective amount of ARA may be from about 5 mg per kg of body weight per day to about 150 mg per kg of body weight per day. In one embodiment of this disclosure, the amount varies from about 10 mg per kg of body weight per day to about 120 mg per kg of body weight per day. In another embodiment, the amount varies from about 15 mg per kg of body weight per day to about 90 mg per kg of body weight per day. In yet another embodiment, the amount varies from about 20 mg per kg of body weight per day to about 60 mg per kg of body weight per day.
  • the LCPUFA source may or may not contain EPA.
  • the LCPUFA used in the disclosure contains little or no EPA.
  • the infant formulas used herein contain less than about 20 mg/100 kcal EPA; in some embodiments less than about 10 mg/100 kcal EPA; in other embodiments less than about 5 mg/100 kcal EPA; and in still other embodiments substantially no EPA.
  • composition of the disclosure is supplemented with oils containing LCPUFAs, it may be accomplished using standard techniques known in the art. For example, an equivalent amount of an oil which is normally present in a composition, such as high oleic sunflower oil, may be replaced with the LCPUFAs.
  • the source of the LCPUFAs can be any source known in the art such as marine oil, fish oil, single cell oil, egg yolk lipid, brain lipid, and the like.
  • the LCPUFAs can be in natural form or refined form.
  • the disclosure provides a commercially acceptable product in terms of desired stability and physical characteristics and the product demonstrates little to no observable browning effect by-products associated with a Maillard reaction. Furthermore, the inventive composition is substantially homogeneous for an acceptable period after reconstitution (or for the shelf-life if prepared as a liquid). The disclosure may be particularly useful for infant formula preparations for the support of retinal, intestinal, and/or nervous system development, although it is equally applicable to other elemental diets specific to a selected population that is at risk of apoptotic neurodegeneration, ROP, and/or NEC.
  • This example illustrates the efficacy of enteral administration of arginine- glutamine dipeptide for the prevention of retinopathy of prematurity in a mouse model of oxygen-induced retinopathy.
  • the C57BL6/J strain of timed pregnant mice was obtained from Jackson Laboratories (Bar Harbor, ME). The mice were housed in the University of Florida Health Science Center Animal Care facilities. The pregnant mice gave birth to the mouse pups used in the experiments.
  • the overall purpose of the experiments in animals is to establish safety, appropriate dosage range, and efficacy prior to evaluation in human neonates at risk for retinopathy of prematurity. Since the ultimate purpose of the arginine- glutamine dipeptide is to provide a safe and easily absorbable preparation that can be used to provide appropriate nutritional intakes of arginine and glutamine in human infants who might not be receiving appropriate quantities of these amino acids in their diets, the dosages in the animal studies are modeled after human premature neonate recommended intakes.
  • mice In the neonatal mouse model of oxygen-induced retinopathy, 7-day old mice are placed with their nursing dams in a 75% oxygen atmosphere for 5 days. Mouse pups receive twice a day gavage feedings of arginine -glutamine dipeptide or control solution (50 ⁇ ) starting on postnatal day 12 (P12) and continuing through postnatal day 17 (P17). Gavage feeds include a control (0.9% sodium chloride) and the test compounds and different doses of arginine-glutamine dipeptide (1.0, 2.5 and 5 g/kg -day). The daily dosage of the dipeptide is divided evenly between the two daily gavage feedings.
  • RNAlater® buffer (Ambion, Austin, TX) at 4°C for subsequent isolation of protein or RNA.
  • mice are taken for qualitative retinal flatmount analysis.
  • the mice are perfused with fluorescein isothiocyanate-labeled dextran to visualize the vasculature.
  • the eyes are enucleated and incubated in 4% formaldehyde and then in phosphate buffered saline cell culture media.
  • the neural retina is dissected from the retinal pigment epithelium -choroid- sclera complex and flatmounted with four to seven radial cuts and examined and photographed separately using confocal microscopy (with a MRC-1024 Confocal Laser Scanning System from Bio-Rad, Hercules, CA).
  • Fig. 1 is a bar chart showing the average nuclei per section in the eyes of neonatal mice exposed to hyperoxia as a function of the dosage of arginine- glutamine dipeptide, with dosage levels of: zero (control); 1 g/kg -day; 2.5 g/kg -day; and 5 g/kg -day.
  • the greater number of nuclei corresponds to greater retinal vascular proliferation and therefore retinopathy.
  • a lower number of nuclei therefore, indicates a more favorable outcome.
  • Fig. 1 it is seen that the average number of nuclei per section was decreased at all levels of administration of the dipeptide as compared with subjects receiving only the control.
  • a recognizable dose/response was shown for dosages of the dipeptide between 1 g/kg -day and 5 g/kg -day, and the highest level of effectiveness was shown at 5 g/kg -day.
  • EXAMPLE 2 This example illustrates the efficacy of enteral administration of arginyl- glutamine dipeptide in protecting against intestinal and brain injury induced by hyperoxia in a mouse model.
  • mice [00077] The C57BL6/J strain of timed pregnant mice was obtained from Jackson Laboratories (Bar Harbor, ME). The mice were housed in the University of Florida Health Science Center Animal Care facilities.
  • mice 7-day old mice are placed with their nursing dams in a 75% oxygen atmosphere for 5 days.
  • Mouse pups receive twice a day gavage feedings of arginine-glutamine dipeptide or control solution (20 pL) starting on postnatal day 12 (P12) and continuing through postnatal day 17 (P17).
  • different dosages of arginine-glutamine dipeptide 1.0, 2.5 and 5 g/kg -day as a hydrochloride salt, Bachem, Babendorf, Switzerland
  • arginine-glutamine dipeptide 5 g/kg -day
  • a normoxia group is used as a control.
  • Tissue total myeloperoxidase (MPO) activity a measure of neutrophil accumulation and a marker of tissue injury.
  • MPO myeloperoxidase activity
  • intestine samples are homogenized on ice in 0.01 M KH2PO4 buffer. After centrifugation at 10,000 g for 20 minutes at 4°C, the pellets are resuspended by sonication in cetyltrimethylammonium bromide buffer (13.7 mM CTAB, 50 mM KH 2 P0 4 , and 50 mM acetic acid, pH 6.0). The supernatant is kept for analysis.
  • the suspension was centrifuged again at 10,000 g for 15 minutes, and the supernatant 1S then incubated in a 60°C water bath for 2 hours.
  • the MPO concentration of the supernatant is measured by the H2O2- dependent oxidation of tetramethylbenzidine.
  • the absorbance is determined at 650 nm and compared with a linear standard curve.
  • the amount of protein is measured using the BioRad Dc Protein Assay (Carlsbad, CA).
  • Bcl-2 levels are determined using standard immunoblotting techniques.
  • the brain was homogenized with a Polytron homogenizer, and the homogenates are stored in aliquots at -80°C.
  • Gel electrophoresis is performed using the BioRad electrophoresis system (Carlsbad, CA). Intestinal protein samples and Kaleidoscope pre-stained protein standards (BioRad, Carlsbad, CA) are loaded on a 12.5% (w V) acrylamide Criterion pre-cast gel (BioRad, Carlsbad, CA) and electrophoresed at 100 volts for about 2 hours.
  • PVDF polyvinyldifluoride membrane
  • NFDM non-fat dried milk
  • Tween-20 Tris-buffered saline containing 0.1% Tween-20 (TBST) (Fisher Scientific, Atlanta, GA).
  • TBST Tris-buffered saline containing 0.1% Tween-20
  • the membranes are washed with multiple changes of TBST and subsequently incubated with a goat-anti-rabbit horseradish peroxidase- conjugated secondary antibody.
  • ECL-PlusTM a chemilumine scent substrate (General Electric Healthcare, Piscataway, NJ) is then applied to the membrane and incubated for 5 minutes at room temperature. Protein bands are visualized by exposure of membrane to X-OMAT scientific imaging film (Eastman- Kodak Corporation, Rochester, NY), followed by development using a Kodak M35A X-OMAT processor (Kodak Diagnostic Imaging Inc., Rochester, NY). Protein bands are quantified by densitometry.
  • Intestinal injury is evaluated using histological techniques.
  • a portion of intestine from the ileum is fixed in 10% (w v) neutral buffered formalin for 24 hours for light microscopy.
  • Caspase-3 activity is determined using a Caspase-3 Colorimetric Activity Assay Kit (Chemicon International, Inc., Temecula, CA). The brain is homogenized with a Polytron homogenizer, and the homogenates are stored in aliquots at -80°C.
  • Fig. 2 is a bar chart showing the intestinal damage score under three different conditions: control; hyperoxic conditions; and hyperoxic conditions combined with arginine-glutamine dipeptide treatment.
  • the damage score decreased when the subject was administered the arginine-glutamine dipeptide.
  • the arginine-glutamine dipeptide protected against intestinal injury with an average damage score of 1.67.
  • the average damage score of intestines exposed to hyperoxic conditions was 3.5.
  • Figs. 3 and 4 are bar charts showing an increased Bcl-2 expression of 33% in a mouse brain treated with arginine-glutamine dipeptide and exposed to hyperoxic conditions.
  • Fig. 4 shows a 32% reduction in brain caspase-3 activity compared to hyperoxic mice.

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Abstract

L'invention porte sur une nouvelle méthode pour soutenir le développement rétinien, intestinal et/ou du système nerveux, chez un nouveau-né. La méthode entraîne l'administration entérale d'un dipeptide arginine-glutamine à un nouveau-né.
PCT/US2010/052585 2009-10-14 2010-10-14 Administration entérale de dipeptide arginine-glutamine pour soutenir le développement rétinien, intestinal ou du système nerveux WO2011047107A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
SG2012016200A SG179040A1 (en) 2009-10-14 2010-10-14 Enteral administration of arginine-glutamine dipeptide to support retinal, intestinal, or nervous system development
CA2777240A CA2777240A1 (fr) 2009-10-14 2010-10-14 Administration enterale de dipeptide arginine-glutamine pour soutenir le developpement retinien, intestinal ou du systeme nerveux
CN2010800460132A CN102573878A (zh) 2009-10-14 2010-10-14 支持视网膜、肠或神经系统发育的精氨酸-谷氨酰胺二肽的肠施用
RU2012119719/15A RU2012119719A (ru) 2009-10-14 2010-10-14 Энтеральное введение аргинин-глутамин дипептида для поддержания развития сетчатки глаз, кишечника и нервной системы
IN2759DEN2012 IN2012DN02759A (fr) 2009-10-14 2010-10-14
BR112012008814A BR112012008814A2 (pt) 2009-10-14 2010-10-14 administração entérica de dipeptídeo arginina-glutamina para suportar o desenvolvimento do sistema retiniano, intestinal ou nervoso.
MX2012003725A MX2012003725A (es) 2009-10-14 2010-10-14 Administracion enteral de un dipeptido de arginina-glutamina para apoyar el desarrollo del sistema retinal, intestinal, o nervioso.
EP10824066A EP2488191A1 (fr) 2009-10-14 2010-10-14 Administration entérale de dipeptide arginine-glutamine pour soutenir le développement rétinien, intestinal ou du système nerveux

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US12/578,922 US20110086809A1 (en) 2009-10-14 2009-10-14 Enteral Administration Of Arginine-Glutamine Dipeptide To Support Retinal, Intestinal, Or Nervous System Development
US12/578,922 2009-10-14

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2612560A1 (fr) 2012-01-09 2013-07-10 N.V. Nutricia Composition nutritionnelle enrichie par glutamine pour les nourrissons prématurés
WO2013105851A1 (fr) 2012-01-09 2013-07-18 N.V. Nutricia Composition nutritionnelle enrichie en glutamine pour nourrissons prématurés
WO2014070016A2 (fr) 2012-11-02 2014-05-08 N.V. Nutricia Combinaison symbiotique pour l'amélioration du cerveau
WO2014109632A1 (fr) 2013-01-09 2014-07-17 N.V. Nutricia Amélioration de la fonction cognitive chez des nourrissons nés avant terme et se révélant petits pour leur âge gestationnel
WO2015160234A1 (fr) 2014-04-17 2015-10-22 N.V. Nutricia Composition d'amélioration de cerveau

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WO2023098537A1 (fr) * 2021-12-01 2023-06-08 盛元医药广州有限公司 Nouvelle utilisation d'alanyl-glutamine et composition ophtalmique comprenant de l'alanyl-glutamine

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US20060229256A1 (en) * 2003-09-26 2006-10-12 Bristol-Myers Squibb Company Enternal administration of arginine and glutamine for abnormal vascular proliferation
US20070054866A1 (en) * 2003-09-26 2007-03-08 Josef Neu Arginyl-glutamine dipeptide for treatment of pathological vascular proliferation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009052106A2 (fr) * 2007-10-14 2009-04-23 University Of Florida Research Foundation Inc. Préparation pour améliorer la fonction gastro-intestinale

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060229256A1 (en) * 2003-09-26 2006-10-12 Bristol-Myers Squibb Company Enternal administration of arginine and glutamine for abnormal vascular proliferation
US20070054866A1 (en) * 2003-09-26 2007-03-08 Josef Neu Arginyl-glutamine dipeptide for treatment of pathological vascular proliferation

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2612560A1 (fr) 2012-01-09 2013-07-10 N.V. Nutricia Composition nutritionnelle enrichie par glutamine pour les nourrissons prématurés
WO2013105852A1 (fr) 2012-01-09 2013-07-18 N.V. Nutricia Composition nutritionnelle enrichie en glutamine pour nourrissons prématurés
WO2013105851A1 (fr) 2012-01-09 2013-07-18 N.V. Nutricia Composition nutritionnelle enrichie en glutamine pour nourrissons prématurés
RU2608232C2 (ru) * 2012-01-09 2017-01-17 Н.В. Нютрисиа Обогащенная глутамином питательная композиция для недоношенных детей
EP3120715A1 (fr) 2012-01-09 2017-01-25 N.V. Nutricia Composition nutritionnelle enrichie par glutamine pour les nourrissons prématurés
WO2014070016A2 (fr) 2012-11-02 2014-05-08 N.V. Nutricia Combinaison symbiotique pour l'amélioration du cerveau
WO2014109632A1 (fr) 2013-01-09 2014-07-17 N.V. Nutricia Amélioration de la fonction cognitive chez des nourrissons nés avant terme et se révélant petits pour leur âge gestationnel
RU2619294C2 (ru) * 2013-01-09 2017-05-15 Н.В. Нютрисиа Улучшение познавательных способностей недоношенных детей, имеющих низкую массу для своего гестационного возраста
WO2015160234A1 (fr) 2014-04-17 2015-10-22 N.V. Nutricia Composition d'amélioration de cerveau
WO2015160256A1 (fr) 2014-04-17 2015-10-22 N.V. Nutricia Composition pour l'amélioration du cerveau

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CN102573878A (zh) 2012-07-11
BR112012008814A2 (pt) 2019-09-24
SG179040A1 (en) 2012-04-27
US20110086809A1 (en) 2011-04-14
IN2012DN02759A (fr) 2015-09-18
CO6531433A2 (es) 2012-09-28
ECSP12011899A (es) 2012-07-31
MX2012003725A (es) 2012-07-10
RU2012119719A (ru) 2013-11-20
CA2777240A1 (fr) 2011-04-21

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